Diabetes
Special Issue
WT Cade, PT, PhD, is Assistant
Professor of Physical Therapy and
Medicine, Washington University
School of Medicine, Campus Box
8502, 4444 Forest Park Blvd, St
Louis, MO 63108 (USA). Address
all correspondence to Dr Cade at:
cadet@wusm.wustl.edu.
[Cade WT. Diabetes-related
microvascular and macrovascular
diseases in the physical therapy
setting. Phys Ther. 2008;88:1322–
1335.]
© 2008 American Physical Therapy
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1322 f Physical Therapy Volume 88
Diabetes-Related Microvascular and
Macrovascular Diseases in the
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Physical Therapy Setting
W Todd Cade
Physical therapists commonly treat people with diabetes for a wide variety of
diabetes-associated impairments, including those from diabetes-related vascular dis-
ease. Diabetes is associated with both microvascular and macrovascular diseases
affecting several organs, including muscle, skin, heart, brain, and kidneys. A common
etiology links the different types of diabetes-associated vascular disease. Common risk
factors for vascular disease in people with diabetes, specifically type 2 diabetes,
include hyperglycemia, insulin resistance, dyslipidemia, hypertension, tobacco use,
and obesity. Mechanisms for vascular disease in diabetes include the pathologic
effects of advanced glycation end product accumulation, impaired vasodilatory re-
sponse attributable to nitric oxide inhibition, smooth muscle cell dysfunction, over-
production of endothelial growth factors, chronic inflammation, hemodynamic dys-
regulation, impaired fibrinolytic ability, and enhanced platelet aggregation. It is
becoming increasingly important for physical therapists to be aware of diabetes-
related vascular complications as more patients present with insulin resistance and
diabetes. The opportunities for effective physical therapy interventions (such as
exercise) are significant.
Number 11 November 2008
 Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy
D
iabetes mellitus (DM) is a
global health issue affecting
children, adolescents, and
adults. According to the World
Health Organization, approximately
180 million people worldwide cur-
rently have type 2 DM (formerly
called adult-onset diabetes); over
95% of people with diabetes have
this form. The number of people
with type 2 DM is estimated to dou-
ble by 2030.1 In the year 2000, death
from diabetes-associated complica-
tions accounted for approximately
6% of worldwide mortality.2 Addi-
tionally, the economic burden of di-
abetes in the United States in 2002
was estimated to be $132 billion.3
Diabetes is a disease that is strongly
associated with both microvascular
and macrovascular complications,
including retinopathy, nephropathy,
and neuropathy (microvascular) and
ischemic heart disease, peripheral
vascular disease, and cerebrovascu-
lar disease (macrovascular), result-
ing in organ and tissue damage in
approximately one third to one half
of people with diabetes.4 Because of
the progressive nature of the disease,
physical therapists will increasingly
encounter patients with prediabetes
(ie, impaired glucose tolerance or
insulin resistance), early type 2 DM
without or with only a few vascular
complications, and more advanced
disease with several vascular compli-
cations. For additional information
describing the epidemiology of these
problems in people with DM, see the
perspective article by Deshpande et
al5 in this issue.
Diabetes-associated vascular alter-
ations include anatomic, structural,
and functional changes leading to
multiorgan dysfunction.6 As physical
therapists increasingly become first-
line providers of treatment for mus-
culoskeletal and movement disorders
in people with diabetes, it will be im-
portant for clinicians to be keenly
aware of the underlying vascular defi-
November 2008
cits in conditions such as diabetic neu-
ropathy, retinopathy, nephropathy,
and cardiovascular and peripheral vas-
cular diseases in their treatment pro-
grams, even if these conditions are
not the reasons for referral. Addition-
ally, physical therapists will play an
important role in the care of people
with diabetes because numerous in-
terventions provided by physical ther-
apists (such as therapeutic exercise)
can assist in alleviating symptoms,
slow the metabolic progression to
overt type 2 DM, and reduce morbid-
ity and mortality associated with these
complications.7–10
Diabetic microvascular (involving
small vessels, such as capillaries)
and macrovascular (involving large
vessels, such as arteries and veins)
complications have similar etiologic
characteristics. Chronic hypergly-
cemia plays a major role in the ini-
tiation of diabetic vascular complica-
tions through many metabolic and
structural derangements, including
the production of advanced glyca-
tion end products (AGE), abnormal
activation of signaling cascades (such
as protein kinase C [PKC]), elevated
production of reactive oxygen spe-
cies (ROS, oxygen-containing mole-
cules that can interact with other
biomolecules and result in damage),
and abnormal stimulation of hemo-
dynamic regulation systems (such as
the renin-angiotensin system [RAS]).
The objectives of this article are to
briefly describe the epidemiology of,
the comorbidities and risk factors as-
sociated with, the pathogenesis of,
and the physical therapy manage-
ment associated with microvascular
and macrovascular complications of
diabetes. In a significant portion of
the article, the term “diabetes” in-
cludes both type 1 DM and type 2
DM, which have much the same vas-
cular pathology and etiology.
Volume 88
Microvascular
Complications of Diabetes
Diabetic Retinopathy
Diabetic retinopathy (DR) is a micro-
vascular complication that can affect
the peripheral retina, the macula, or
both and is a leading cause of visual
disability and blindness in people
with diabetes.1 The severity of DR
ranges from nonproliferative and
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preproliferative to more severely
proliferative DR, in which the abnor-
mal growth of new vessels occurs.11
Total or partial vision loss can occur
through a vitreous hemorrhage or
retinal detachment, and central vi-
sion loss can occur through retinal
vessel leakage and subsequent mac-
ular edema.12 The prevalence of DR
increases with prolonged duration of
diabetes.13 In studies including peo-
ple with both type 1 diabetes and
type 2 diabetes, after 30 years of di-
abetes, most patients had some form
of DR, and over half had proliferative
DR; people with type 1 diabetes and
taking insulin had the highest preva-
lence of DR, and people with type 2
diabetes diagnosed after age 30 had
the lowest prevalence of DR.14 –16
Diabetic retinopathy also recently
was seen in approximately 10% of
people with insulin resistance (pre-
diabetes) and was associated with
the presence of hypertension and a
higher body mass index.17 Other
studies of DR showed associations
with younger age of onset, tobacco
use, insulin treatment, abnormal
blood lipid (ie, total cholesterol, low-
density lipoprotein [LDL], and tri-
glyceride) levels, pregnancy, renal
disease, elevated homocysteine lev-
els,18 and a diet high in fat
(Table).19 –21
The earliest histological marker of
DR is the loss of pericytes.22 Peri-
cytes are elongated contractile cells
that wrap around endothelial cells of
small vessels23 and assist in providing
maintenance of capillary tone (ie, di-
latation and constriction),24 capillary
Number 11 Physical Therapy f 1323
Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy

Table.
Risk Factors for Diabetes-Associated Microvascular and Macrovascular Complications

Peripheral
Cardiovascular Cerebrovascular Vascular
Risk Factor Retinopathy Neuropathy Nephropathy Disease Disease Disease

Hyperglycemia Yes Yes Yes Yes Yes Yes

Hyperinsulinemia Yes

Age Yes Yes Yes Yes

Tobacco use Yes Yes Yes Yes Yes

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Insulin treatment Yes

Dyslipidemia Yes Yes Yes Yes

Pregnancy Yes

Renal disease Yes

Elevated homocysteine level Yes

High-fat diet Yes

Chronic diabetes mellitus Yes Yes

Hypertension Yes Yes Yes Yes

Obesity Yes Yes

Atrial fibrillation Yes

Heart failure Yes

Proteinuria Yes Yes

Microalbuminuria Yes Yes Yes

Hyperuricemia Yes

Blood inflammatory Yes

molecules

Elevated blood fibrinogen Yes

level

Physical inactivity Yes Yes

Elevated height Yes

Ketoacidosis Yes

Carotid artery stenosis Yes

growth, and protection against ROS
damage.25 Therefore, the loss of peri-
cytes with DR would interfere with
capillary constriction (producing
chronically dilated vessels), new capil-
lary generation, and processes that
protect vessels against continuous ex-
posure to noxious molecules (ie, nor-
mal homeostasis). Other microvascu-
lar changes that occur with DR in-
clude capillary basement membrane
thickening (Fig. 1),26 increased per-
meability of endothelial cells, and for-
mation of microaneurysms (ie, weak-
ening of vessel walls that results in
the projection of a balloonlike sac)
(Fig. 2).27
The most significant factor in the de-
velopment and progression of DR in
people with diabetes appears to be
poor glycemic (blood sugar) con-
trol.28,29 Under hyperglycemic con-
ditions, which are frequently seen in
people with diabetes, impairment of
retinal blood flow, increased inflam-
matory cell adhesion to retinal blood
vessels, and capillary blockage can
result in hypoxia and damage to the
retina.30
Diabetic Neuropathy
Approximately one half of people
with diabetes have some form of
peripheral neuropathy (PN), either
polydiabetic or monodiabetic neu-
ropathy.31 People with diabetes also
frequently have autonomic neuropa-
thy, including cardiovascular auto-
nomic dysfunction, which is mani-
fested as abnormal heart rate (HR)
and vascular control.32 Physical ther-
apists commonly encounter diabetes-
associated PN in the evaluation and
treatment of balance and movement
disorders because these disorders fre-
quently affect lower-extremity sensa-
tion and can cause lower-extremity
pain in people with diabetes. Loss of
lower-extremity sensation coupled
with impaired peripheral vascular
function can contribute to lower-

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 Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy

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Figure 1.
Representative transmission electron micrographs of capillary basement membranes (opposing arrows) in tissues from 300- to
350-day-old normal mice (a) and age- and sex-matched transgenic diabetic mice (b). Capillary basement membranes are shown in
renal glomerulus (1a, 1b), retina (2a, 2b), and peripheral nerve (6a, 6b). All micrographs: ⫻28,500. Reprinted with permission of
Wiley-Liss Inc, a subsidiary of John Wiley & Sons Inc, from: Carlson EC, Audette JL, Veitenheimer NJ, et al. Ultrastructural morphometry
of capillary basement membrane thickness in normal and transgenic diabetic mice. Anat Rec A Discov Mol Cell Evol Biol. 2003;271:
332–341.

extremity (commonly foot) ulcer-
ation.33 Like those for DR, the risk fac-
tors for PN include poor glycemic
control (ie, elevated glycation hemo-
globin levels and impaired glucose tol-
erance34), age, duration of diabetes,
tobacco use, dyslipidemia, and hyper-
tension (especially diastolic) (Table).35
Other independent risk factors for PN
include increased height, presence of
cardiovascular disease (CVD), pres-
ence of severe ketoacidosis (ie, ele-
vated by-products of fat metabolism in
the blood), and presence of mi-
croalbuminuria (ie, presence of albu-
min in urine, indicating early renal dys-
function) (Table).36 Unlike that of DR,
the pathogenesis of PN appears to be
related to both vascular and nonvascu-
lar metabolic mechanisms, but this
theory is controversial.37–39 For addi-
tional information related to the ef-
fects of peripheral neuropathy on skin
and muscle, see related articles by
Mueller et al,40 LeMaster et al,41 and
Hilton et al42 in this issue.
Characteristic traits of PN include ax-
onal thickening with progression to
axonal loss,43 basement membrane
thickening, pericyte loss,44,45 loss of
microfilaments (ie, cytoskeletal fila-
ments comprising actin and myosin),
and decreased capillary blood flow
to C fibers,46 leading to decreased
nerve perfusion and endoneurial
hypoxia44,45 (Fig. 1). Neuronal mi-
crovasculature is impaired in the
presence of hyperglycemia,47 and
this impairment is mediated through
the abnormal initiation of signaling
cascades,48,49 potentially leading to
the demyelination associated with di-
abetic PN.50 Both nonvascular and
vascular mechanisms of PN appear
to be primarily related to the meta-
bolic aspects (ie, hyperglycemia) of
diabetes.

November 2008 Volume 88 Number 11 Physical Therapy f 1325

Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy
Figure 2.
Microaneurysms in diabetic retinopathy. From the Slice of Life collection, curated by
Suzanne Stensaas, University of Utah.
Diabetes-related cardiac autonomic
neuropathy is frequently underdiag-
nosed and can include clinical ab-
normalities such as resting tachy-
cardia, exercise intolerance, resting
HR variability, slow HR recovery
after exercise, orthostasis, “silent”
myocardial infarction, and increased
risk of mortality.51,52 The prevalence
of diabetes-related cardiac auto-
nomic neuropathy is unclear and has
been reported to range from 1% to
90%, depending on the outcome
variable.32 Risk factors for diabetes-
associated cardiac neuropathy in-
clude age, obesity, smoking, poor
glycemic control, and hypertension
(Table).53
Cardiac autonomic dysfunction in
people with diabetes has been asso-
ciated with diabetic cardiomyopa-
thy, a topic beyond the scope of this
article. In brief, people with diabetic
cardiomyopathy have diastolic filling
and relaxation abnormalities fre-
quently later accompanied by sys-
tolic dysfunction and heart failure. It
is unclear whether cardiac auto-
nomic dysfunction directly mediates
diabetic cardiomyopathy, because
1326 f Physical Therapy Volume 88
many of the same risk factors and
mechanisms contribute to the devel-
opment of both conditions.51
Diabetic Nephropathy
Diabetic nephropathy (DN) is a seri-
ous and progressive complication of
both type 1 DM and type 2 DM. The
first manifestation of DN is typically
microalbuminuria, which progresses
to overt albuminuria (ie, increased
albumin levels in the urine, indicat-
ing more severe renal dysfunction)
and eventually to renal failure54 and
is the leading cause of end-stage re-
nal disease (ESRD).55 Approximately
one fourth of people with type 2
diabetes have microalbuminuria or a
more advanced stage of DN that
worsens at a rate of 2% to 3% per
year.56 Other characteristic features
of DN include thickening of glomer-
ular basement membranes (Fig. 1)
and glomerular hyperfiltration, leading
to mesangial (central part of the renal
glomerulus) extracellular matrix ex-
pansion and further increases in uri-
nary albumin excretion57 and pro-
gressing to glomerular and tubular
sclerosis and renal failure.58,59 Like
those for DR and PN, the risk factors
Number 11
for DN include hyperglycemia, dura-
tion of diabetes, age of onset, tobacco
use, dyslipidemia, hypertension,60,61
and obesity (Table).62
Macrovascular
Complications of Diabetes
Cardiovascular disease (CVD) is the
leading cause (⬃70%) of death in
people with type 2 diabetes.63,64 Peo-
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ple with diabetes have a 4-fold-
greater risk for having a CVD event
than people without diabetes after
controlling for traditional risk factors
for CVD, such as age, obesity, to-
bacco use, dyslipidemia, and hyper-
tension.65,66 These CVD risk factors
are common in diabetes, but data
suggest that diabetes is an indepen-
dent risk factor for CVD. People with
diabetes also have a 5-fold-greater
risk for a first myocardial infarction
(MI) and a 2-fold-greater risk for a
recurrent MI than people who previ-
ously had an MI but do not have
diabetes. These data suggest that the
risk for an MI in people who have
diabetes but who have not had an MI
is similar to that in people without
diabetes but with a previous MI.67
Further, people with diabetes have a
poorer long-term prognosis after an
MI, including an increased risk for
congestive heart failure and death.68
Even people with insulin resistance
(ie, the blunted response of tissues
[such as muscle, fat, and liver] to
insulin that frequently precedes type
2 DM) have an increased risk for
CVD.69 Traditionally, diabetes and
CVD were limited primarily to West-
ernized populations. However, re-
cent evidence suggests that these
conditions are rapidly emerging in
resource-limited regions of the
world,70 and estimates indicate that
80% of people with diabetes world-
wide will die from CVD.71
People with diabetes (particularly
type 2 DM) frequently have many
traditional risk factors for CVD, in-
cluding central obesity, dyslipidemia
(ie, elevated serum triglyceride, LDL,
November 2008
 Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy
and free fatty acid levels and low
high-density lipoprotein levels), and
hypertension.72 The combination of
central adiposity, dyslipidemia, hy-
perglycemia, and hypertension in
the general population is termed
“metabolic syndrome.”73 These fac-
tors, along with the independent risk
factor of diabetes, can act both inde-
pendently and cumulatively over
time to significantly increase risk for
CVD. The combination of hypergly-
cemia, insulin resistance, dyslipide-
mia, hypertension, and chronic in-
flammation can injure the vascular
endothelium, leading to macrovascu-
lopathy and CVD in people with type
2 DM.74
Cerebrovascular Disease
Stroke is the third leading cause of
death in the United States, after CVD
and cancer,75 and is an event very fa-
miliar to physical therapists. Diabetes
is an independent risk factor across all
ages76 for stroke; the risk in people
with diabetes is up to 2- to 4-fold
greater, more so in white people and
women.75,77–79 Diabetes is also a risk
factor for sudden and eventual death
from stroke,80,81 and people who have
diabetes and who have a stroke have
more severe neurological deficits and
disability,82– 84 a poorer long-term
prognosis,85 and a higher incidence of
stroke recurrence than people with-
out diabetes.86
As in CVD, the presence of diabetes
adversely affects the cerebrovascular
circulation by increasing the risk of
intracranial and extracranial (eg, ca-
rotid artery) atherosclerosis.87,88 Peo-
ple with diabetes have an increased
incidence of traditional risk factors
for stroke, including hypertension,
dyslipidemia, heart failure, and atrial
fibrillation.89 However, after these
factors are controlled for, diabetes
remains a strong predictor for
stroke, suggesting that the presence
of diabetes carries an independent
risk for stroke apart from the in-
November 2008
creased presence of traditional risk
factors (Table).80
As in other diabetes-related compli-
cations, hyperglycemia appears to be
a significant factor in stroke. Hyper-
glycemia is a significant predictor of
fatal and nonfatal stroke90 and death
from stroke.91 Hyperinsulinemia (ie,
elevated blood insulin levels) also
appears to be a risk factor for
stroke,92,93 although this relationship
is still unclear.94 The presence of DR,
proteinuria, microalbuminuria, and
hyperuricemia (ie, elevated blood
uric acid levels) are other diabetes-
related factors associated with an in-
creased risk for stroke (Table).91,95,96
Finally, elevated blood levels of
chronic inflammatory markers are as-
sociated with an increased risk for
stroke in people with diabetes.97
Peripheral Artery Disease
Currently in the United States, more
than 3.5 million people (African-
American ⬎ white ⬎ Hispanic peo-
ple) with diabetes have peripheral
artery disease (PAD).98 Peripheral
artery disease is characterized by
occlusion of the lower-extremity ar-
teries,99 which can cause intermittent
claudication and pain, especially upon
exercise and activity,100 and which
can result in functional impairments101
and disability.102 Physical therapists
frequently encounter people with
diabetes-related PAD because of these
functional impairments and because
of common events of more severe PAD:
foot ulceration and lower-extremity
amputation.103 Because people with
diabetes are 15 times more likely to
have lower-extremity amputation than
people without diabetes,104 physical
therapists frequently treat people
with diabetes-related amputations. As
the incidence of diabetes increases,
physical therapists will more fre-
quently see, treat, and prescribe ex-
ercise for these people. An elevated
awareness of PAD is needed among
physical therapists because death in
people with diabetes and PN is fre-
Volume 88
quently attributed to CVD.105 More-
over, lower-extremity amputation is
more common in people with dia-
betes and PAD than in people with-
out diabetes but with PAD106; these
data suggest that physical thera-
pists should carefully assess lower-
extremity blood flow (ie, peripheral
pulses) and skin integrity for all pa-
tients with diabetes, especially those
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with known PAD.
Peripheral artery disease, like the
aforementioned vascular diseases, is
related to the duration and severity
of diabetes.106,107 Hyperglycemia, spe-
cifically, glycation hemoglobin, has
been shown to be an independent risk
factor for PAD.108 In addition to dia-
betes, other risk factors for PAD in-
clude hypertension, tobacco use, obe-
sity (ie, waist-to-hip ratio), elevated
serum fibrinogen levels, dyslipidemia,
a history of CVD, and physical inactiv-
ity (Table).109,110
Common Mechanisms for
Microvascular and
Macrovascular Diseases
in Diabetes
One common pathogenic mecha-
nism for microvascular disease is
rooted in chemical reactions be-
tween by-products of sugars and pro-
teins that occur over the course of
days to weeks and eventually pro-
duce irreversible cross-linked pro-
tein derivatives called AGE.111 These
derivatives can exhibit a wide range
of effects on surrounding tissues, in-
cluding modification (eg, thicken-
ing) of collagen112 and endotheli-
um.113 Specifically, in DR, AGE can
induce growth inhibition and pro-
grammed cell death (ie, apoptosis) of
retinal pericytes,114 induce overpro-
duction of endothelial growth fac-
tors (including vascular endothelial
growth factor, insulin-like growth
factor 1, basic fibroblast growth fac-
tor, and hepatocyte growth fac-
tor),115,116 increase pathologic angio-
genesis (neovascularization),117 and
Number 11 Physical Therapy f 1327
Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy
Figure 3.
Potential mechanisms for diabetes-associated endothelial dysfunction. AGE⫽advanced
glycation end products, RAGE⫽receptors for AGE, ROS⫽reactive oxygen species,
PKC⫽protein kinase C, RAS⫽renin-angiotensin system, FFA⫽free fatty acid.
increase vascular inflammation118; all
of these actions lead to an increased
risk for microthrombosis formation,
capillary blockage, and retinal isch-
emia.119 Neovascularization, vitreous
hemorrhage, and increased levels of
vascular endothelial growth factor
can further lead to retinal fibrosis
and detachment and loss of vision.12
In addition, AGE can bind to immu-
noglobulin protein receptors for
AGE and produce a cascade of sig-
naling events that lead to endothelial
cell dysfunction120 (Fig. 3).
1328 f Physical Therapy Volume 88
Advanced glycation end products
also play a role in DN through AGE-
mediated programmed cell death of
mesangial cells and altered extracel-
lular matrix proteins that appear to
contribute to both glomerular hyper-
filtration116 and sclerosis.121 The for-
mation of AGE also may stimulate the
oversecretion of growth factors such
as insulin-like growth factor 1 and
transforming growth factor ␤ and
further contribute to glomerular fi-
brosis,122 leading to a decrease in
available glomerular surface area for
filtration.123
Number 11
Other mechanisms involved in mi-
crovascular disease include the PKC
pathway (a family of multifunctional
enzymes involved in signal transduc-
tion and gene expression of growth
factors and inflammatory signals124
that may increase vascular perme-
ability) and the polyol pathway (the
enzymes aldose reductase and sorbi-
tol dehydrogenase, which catalyze
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reactions that can lead to sorbitol
accumulation-associated osmotic and
oxidative stress damage to the endo-
thelium125) (Fig. 3). Peripheral nerve
damage in DN, including neuronal
degeneration and impairment of re-
generation of thinly myelinated fi-
bers, is also mediated by AGE accu-
mulation, the activation of the polyol
and PKC pathways, and the deleteri-
ous effects of ROS.126,127
Additionally, the RAS128 plays a role
in microvascular disease because it
can alter glomerular hemodynamics
and mediate sclerosis in DN. Other
enzymatic pathways are involved in
the development and progression of
microvascular disease but are not dis-
cussed here. For an in-depth discus-
sion of these pathways, see more de-
tailed reviews.129,130
The pathogenesis of macrovascular
disease in diabetes is multifactorial;
however, the common recipient of
injury is the vascular endothelium
(Fig. 4). Diabetes initially impairs the
ability of the vascular endothelium to
vasodilate through inhibition of the
nitric oxide (NO, a gas molecule that
maintains arteriolar vasodilatation)
pathway.131 The presence of hyper-
glycemia inhibits the enzyme re-
sponsible for the production of NO
(ie, endothelial nitric oxide synthase
[eNOS]) and increases the produc-
tion of ROS, leading to further inhi-
bition of eNOS.132,133 The vascular
endothelium also loses its ability to
produce NO-activated tissue plas-
minogen activator, a fibrinolytic
(anti-clotting) protein that inhibits
the ability of inflammatory cells to
November 2008
 Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy
Figure 4.
Potential mechanisms for diabetes-associated vascular abnormalities. NO⫽nitric oxide, tPA-1⫽tissue plasminogen activator-1,
PAI-1⫽plasminogen activator inhibitor-1.
“stick” to the endothelial surface.134
Insulin resistance also can contribute
to a decrease in NO production and
the subsequent impaired vasodila-
tory response. In addition, insulin re-
sistance can lead to an increase in
the release of free fatty acids from
adipose tissue135 and stimulate the
PKC pathway, which can directly
and indirectly inhibit eNOS activity
through increased ROS generation.136
The production of AGE (from hy-
perglycemia) also inhibits NO pro-
duction, further impairing the vaso-
dilatory response in diabetes.137 In
addition to the reduction in the va-
sodilatory response in diabetes, an
overproduction of vasoconstrictor
substances occurs; these substances
include endothelin 1, which has di-
rect vasoconstrictive effects on the
endothelium as well as indirect fluid
volume effects, including the stimu-
lation of water and salt retention and
the activation of the RAS.138
November 2008
Another factor involved in the devel-
opment and progression of macrovas-
cular disease in diabetes is impaired
platelet function, which may lead to
increased risks for thrombus forma-
tion, atherosclerosis progression, and
plaque rupture.134 Hyperglycemia-
stimulated PKC pathway effects on
NO and ROS generation and diabetes-
associated impaired fibrinolytic capacity
may contribute to this increased co-
agulative state.139,140 Another diabetes-
related mechanism for macrovascular
disease is a hyperinflammatory state.
Inflammatory cells (eg, monocytes and
T lymphocytes) enter damaged en-
dothelial cells and migrate into the
deeper layers (intima media) of ves-
sels, ingesting oxidized LDL and form-
ing foam cells.141 Foam cells are the
central component of atherosclerotic
fatty streaks, an early marker of mac-
rovascular disease (Fig. 2). The levels
of adhesion molecules (ie, proteins
that recruit inflammatory cells) are
Volume 88
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also elevated in people with diabetes,
thereby facilitating the process of
foam cell formation.142 Finally, diabe-
tes is associated with smooth muscle
cell dysfunction.74 Although the pre-
cise mechanism for smooth muscle
cell dysfunction in diabetes is unclear,
it may be associated with similar
mechanisms for endothelial cell dys-
function, including activation of the
PKC pathway, AGE deposition, and
AGE receptor activation as well as
overproduction of growth factors.136
In the development of atherosclerosis,
activated smooth muscle cells in the
medial layer of arteries migrate to the
atherosclerotic fatty streaks in the in-
timal layer and produce an extensive
extracellular matrix, solidifying the
streaks and reciprocally reducing the
protective strengthening function in
the medial layer, making the athero-
sclerotic plaque unstable and prone
to rupture.143 These hyperglycemia-
stimulated events act in conjunction
Number 11 Physical Therapy f 1329
Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy
over time to produce atheroma and
eventual atherosclerosis.72
Many of the mechanisms for CVD
appear to affect the cerebrovascula-
ture in a similar manner, but this
theory is under debate.144 How-
ever, a unique effect of diabetes on
neurons and glial cells occurs dur-
ing ischemia (such as during a tran-
sient ischemic attack or stroke). This
relationship has been demonstrated
through the relationship between
hyperglycemia and increased intra-
cellular acidosis.145 Neuronal intra-
cellular acidosis occurs during an
ischemic event as a result of ele-
vated anaerobic metabolism, which
leads to neuron and glial cell dam-
age.145,146 Acidosis may induce intra-
cellular damage through ROS genera-
tion, intracellular signaling disruption,
and activation of DNA-splitting en-
zymes.146 Hyperglycemia also is asso-
ciated with increased levels of excita-
tory amino acids (eg, glutamate),
which may induce neuronal cell death
through the activation of glutamate re-
ceptors, the influx of excess calcium,
and mitochondrial (cell energy power-
house) injury.146,147 This process may
lead to a poorer outcome of stroke in
people with diabetes.
Role of Physical Therapists
in Diabetes-Related
Microvascular and
Macrovascular Diseases
Diabetes-related comorbidities are
conditions that physical therapists
will encounter during the evaluation
and treatment of movement and
functional disorders in people with
diabetes. Besides improving move-
ment and function, in general, phys-
ical therapists may improve the qual-
ity of life for people with diabetes
and macrovascular and microvascu-
lar diseases through the use of inter-
ventions that address pain, poor en-
durance, obesity, and increased risk
for microvascular and macrovascular
diseases. Specifically, the prescrip-
1330 f Physical Therapy Volume 88
tion and monitoring of an individual-
ized exercise program are essential
in a management program, regard-
less of the severity of diabetes. Exer-
cise therapy may greatly benefit
many patients with diabetes by re-
ducing hyperglycemia, insulin resis-
tance, dyslipidemia, and hyperten-
sion; these reductions may translate
into an improved vascular disease
risk profile in children, adolescents,
and adults with diabetes.148 –150 Exer-
cise also may aid in weight loss, spe-
cifically, loss of trunk fat, and also
may improve glycemic and lipemic
control in people with diabetes.151
Additionally, exercise may improve
physical function152 and quality of
life in people with diabetes.153 Cau-
tion should be observed in patients
who have proliferative DR, micro-
albuminuria, and cardiac autonomic
dysfunction and who are starting
aerobic exercise programs, because
exercise, particularly resistance ex-
ercise, increases retinal blood pres-
sure, reduces kidney blood flow, and
stresses autonomic control of HR
and contractility.154 For additional in-
formation related to the metabolic
effects of exercise in people with DM,
see related articles by Turcotte and
Fisher155 and Gulve156 in this issue.
A frequent progression of DN, ESRD,
is a significant cause of functional
impairments and disability157 in peo-
ple with diabetes and an area in
which physical therapists may play
an increasing role in the treatment of
these consequences, because exer-
cise training appears to improve
functional and work capacities and
increase independence in these peo-
ple.158,159 People with ESRD fre-
quently have a low hematocrit and
muscle atrophy,160 which may con-
tribute to their reduced exercise ca-
pacity and disability.161 An impaired
glomerular filtration rate has been as-
sociated with low exercise capaci-
ty162 and low activity levels.163 Exer-
cise training has been shown to
Number 11
improve markers of DN, specifically
decreasing microalbuminuria.164
Peripheral artery disease is another
condition that physical therapists fre-
quently encounter in patients with
diabetes. The clinical evaluation of
PAD in people with diabetes com-
monly involves palpating for periph-
eral arterial pulses, but this tech-
Downloaded from https://academic.oup.com/ptj/article-abstract/88/11/1322/2858152 by guest on 04 November 2018
nique has been shown to have poor
accuracy for the determination of
PAD.165 The ankle brachial index
(ABI), a sensitive and specific test for
determining PAD,166 is performed by
measuring systolic blood pressure in
the upper (brachial artery) and
lower (dorsalis pedis and posterior
tibialis arteries) extremities with a
hand-held Doppler probe and divid-
ing the higher ankle systolic pressure
by the higher brachial artery pres-
sure.167 An ABI of less than 0.90 is
predictive of PAD, and an ABI of less
than 0.50 is associated with impaired
physical function (such as walking
distance).166 Although a Doppler
probe is not commonly used in the
physical therapy setting, clinics that
frequently treat people with
diabetes-associated PAD may benefit
from using this relatively inexpen-
sive tool because it may provide di-
agnostic and treatment monitoring
criteria. Other clinical testing in pa-
tients with diabetes-associated PAD
may include treadmill testing168 or
the 6-minute walk test169 to deter-
mine walking capacity and time to
claudication and pain, if present. Su-
pervised exercise training in people
with PAD has been shown to be
highly beneficial in terms of walking
distance and time, time to claudication
and pain, and quality of life170,171; is
more effective than pharmacologic
therapy172; and is considered to be
first-line therapy in the treatment of
PAD.168 Accordingly, physical thera-
pists are becoming first-line treatment
providers for patients with diabetes-
related PAD and should be strong ad-
vocates of exercise treatment for these
patients.
November 2008
 Diabetes-Related Microvascular and Macrovascular Diseases in Physical Therapy
The clinical evaluation and treatment
of DN, a common condition in the
physical therapy setting, require
more specificity. The evaluation of
diabetic PN in the clinical setting in-
volves a variety of tests, which may
include the measurement of periph-
eral (typically of the lower extrem-
ity, such as the foot) light touch and
vibration sense as well as nerve bi-
opsy.173 The clinical evaluation of vi-
bration sense, a test frequently used
in the physical therapy setting, is the
strongest predictor of foot insensitiv-
ity ulceration.174 Electrophysiologic
nerve conduction testing, occasion-
ally performed in physical therapy
clinics but more often performed in
physicians’ offices, is considered to
be the gold standard for measuring
nerve function.175 Nerve biopsy is
not considered part of routine clini-
cal testing in DN; however, skin bi-
opsy testing is becoming more fre-
quent in clinics. Skin biopsy testing
is minimally invasive and may pro-
vide important information, such as
nerve density and small-fiber neurop-
athy,176 and it may be useful in pre-
dicting the progression of the
disease.177 A newly developed non-
invasive technique for assessing the
presence of DN is corneal confocal
microscopy, with which the density
and length of the corneal nerve have
been shown to be strongly associ-
ated with lower-extremity nerve
density and which is gaining in pop-
ularity.37 These clinical measure-
ments also may be used to assess the
efficacy of specific interventions, in-
cluding medications, exercise, and
weight loss.
Clinical tests to evaluate diabetes-
associated cardiac autonomic neu-
ropathy include measurement of
resting HR, exercise testing, mea-
surement of blood pressure in re-
sponse to postural changes (such as
moving from a supine position to a
standing position), autonomic reflex
testing, measurement of 24-hour HR
variability, spontaneous baroreflex
November 2008
sensitivity testing, and cardiac radio-
nuclide imaging.51 Several of these
tests, including HR and blood pres-
sure responses to exercise and pos-
tural changes, can be performed in
the physical therapy setting. A rest-
ing HR of ⱖ100 beats per minute is
considered to be tachycardia in
adults. Orthostatic hypotension is
defined as a decrease of greater than
30 mm Hg in systolic blood pressure
and a decrease greater than 10 mm
Hg in diastolic blood pressure in re-
sponse to a change from a supine
position to a standing position.178 Pa-
tients with diabetes-associated car-
diac autonomic neuropathy have a
blunted HR response to exercise (ie,
they do not attain the age-predicted
maximal HR) and a slow HR recovery
after peak exercise52; the latter is
predictive of CVD and all-cause mor-
tality.52 Physical therapists, therefore,
may have to rely more on the patient’s
perceived exertion than on HR re-
sponses for exercise prescription.179
Conclusion
Diabetes is associated with both mi-
crovascular and macrovascular dis-
eases affecting numerous organs, in-
cluding skeletal muscle, skin, heart,
brain, and kidneys. Common patho-
genic mechanisms link the differ-
ent types of diabetes-associated vas-
cular disease (such as CVD and PAD).
Common risk factors for vascular
disease in diabetes include hypergly-
cemia, insulin resistance, dyslipide-
mia, hypertension, tobacco use, and
obesity.
Mechanisms for microvascular dis-
ease in diabetes include the patho-
logic effects of AGE accumulation,
overproduction of endothelial growth
factors, and abnormal stimulation of
the PKC and polyol pathways and
the RAS. Mechanisms for macro-
vascular disease in diabetes include
the pathologic effects of AGE accu-
mulation, impaired vasodilatory re-
sponse attributable to NO inhibi-
tion, smooth muscle cell dysfunction,
Volume 88
overproduction of endothelial growth
factors, chronic inflammation, he-
modynamic dysregulation, impaired
fibrinolytic ability, and enhanced
platelet aggregation (clotting). It is
becoming increasingly important for
physical therapists to be aware of
diabetes-related vascular complications
as more patients present with insulin
resistance and type 2 DM. The oppor-
Downloaded from https://academic.oup.com/ptj/article-abstract/88/11/1322/2858152 by guest on 04 November 2018
tunities for effective physical therapy
interventions (such as exercise) are
significant.
This work was supported by National Insti-
tutes of Health grant K0K074343A.
This article was submitted January 8, 2008,
and was accepted May 6, 2008.
DOI: 10.2522/ptj.20080008
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